Process for nitrosamine-free sabilized isothiazolones

ABSTRACT

Nitrosamine-free 3-isothiazolone biocidal compositions suitable for applications where substantial human or animal contact is anticipated, their method of use and process of preparation are disclosed.

This is a divisional of application Ser. No. 376,199, filed July 3, 1989now U.S. Pat. No. 4,939,266 which was in turn a continuation of Ser. No.383,858 file on June 1, 1982 now abandoned.

This invention is directed to 3-isothiazolone compositions containinglittle or no nitrosamine impurities making them especially suitable forcosmetic and drug applications, their method of use and the processes bywhich the products are made nitrosamine-free.

The 3-isothiazolones comprise a large group of biologically activepesticides exhibiting biostatic and/or biocidal activity towards manypests of both animal and vegetable origin, such as fungi, bacteria,algae, slime, barnacles, mildew and the like (see U.S. Pat. No.3,761,488). These compounds may be represented by the following generalformula: ##STR1## wherein R and R' are independently selected fromhydrogen, halogen or an alkyl group of 1 to 4 carbon atoms; Y is analkyl group of 1 to 8 carbon atoms, a cycloalkyl group of 3 to 6 carbonatoms, an aralkyl group of up to 8 carbon atoms, or an aryl orsubstituted aryl group of 6 carbon atoms.

When the 3-isothiazolone is one in which Y (see formula above) is loweralkyl, and at least one of R and R' is halogen (with the other, usuallyR, a hydrogen), the compounds are useful industrial biocides havingalmost unlimited solubility in water (see U.S. Pat. No. 4,105,431). Theless water-soluble, higher alkyl 3-isothiazolones are generally usefulas mildewcides and fungicides in organic solutions and emulsion productssuch as paints; the higher alkyl isothiazolones are soluble in variousorganic solvents such as ethanol, isopropanol, acetone and the like.Such solutions may be easily extended with water. Isothiazolones arealso used in solid form, preferably absorbed on or in a particulatecarrier.

Unfortunately, solutions of the 3-isothiazolones, especially aqueoussolutions or solutions in polar organic solvents such as alcohols, areunstable, leading to reduced biological effectiveness.

This is especially true of the lower alkyl analogs, that is, where Yabove is a C₁ -C₄ alkyl or a cycloaliphatic radical. The instabilityresults from an opening of the isothiazolone ring to form linearcompounds which do not have the same biological properties as the ringcompounds. To inhibit ring cleavage, nitrate salts, particularly thoseof polyvalent metals such as calcium, copper, magnesium, manganese,nickel and zinc, can be added to isothiazolone solutions. Thus it iscommercially desirable today to formulate many of the 3-isothiazolonebiocides in solutions containing water or organic solvent or mixturesthereof together with nitrate stabilizers to prevent decomposition ofthe 3-isothiazolone (see U.S. Pat. No. 3,870,795).

The effectiveness of the 3-sothiazolone biocides at very low use levelshas encouraged further commercial use in products intended for humancontact such as topically applied cosmetics, thus creating greaterrequirements for purity than previously needed for industrialapplications.

The existing commercial process used for manufacturing 3-isothiazoloneshas included amidation of a disulfide followed by the halogenationcyclization of the disulfide amide: ##STR2## wherein X and Z (R and R'in the general formula, except for halogen later attached) are hydrogenor lower alkyl and Y is as set forth in the above general formula.

Cyclization is accomplished by contacting the amide with a halogenatingagent. Typical halogenating agents include chlorine, bromine, sulfurylchloride, sulfuryl bromide, N-chlorosuccinimide, N-bromosuccinimide, andthe like. Chlorine and sulfuryl chloride are the preferred halogenatingagents. For most industrial purposes the amidation of the disulfideintermediate (hereinafter "disulfide") produces the amide intermediates(hereinafter "amide") and ultimately the 3-isothiazolone compounds ofrelatively high purity. When prepared according to the above reactions(A) and (B), the 3-isothiazolones are generally mixtures comprising twoor more active ingredient (AI) isothiazolone species together withvarious by-products, including some amines which have not heretoforebeen characterized. The term "isothiazolone" is alternatively usedherein and in the claims to refer to individual species or,collectively, to refer to reaction mixtures comprising a plurality ofbiologically active compounds.

We have now discovered that certain 3-isothiazolone biocides producedusing the prior art disulfide intermediate may contain by-productimpurities having a secondary or tertiary amine group which, uponexposure to nitrosating conditions, can be converted to nitrosocompounds. As a group, nitroso compounds are generally suspected to bepossible carcinogens. Accordingly, it is desirable to find means foreliminating even the trace quantities of those by-product impuritieswhich serve as precursors to the formation of nitrosamines, especiallyfor products to be used in applications where human or animal contact isanticipated.

The nitrosamine problem is exacerbated when formulating 3-isothiazolonecompositions in solutions, either aqueous solutions or organic solutionsor mixtures thereof wherein it is necessary to incorporate a nitratesalt, see, e.g., U.S. Pat. No. 4,067,878, or where another nitrosatingagent may be present in the isothiazolone. When the metal nitrate saltis present as a stabilizer, any by-product secondary or tertiary aminecompound present in the 3-isothiazolone reaction mixture is subject tobeing nitrosated to a nitroso compound which may be suspected to becarcinogenic. The expression "nitrosamine precursor", or simply"precursor", is intended to identify a secondary amine (and if present,a tertiary amine) by-product compound which can be converted to anitrosamine.

It is an object of this invention to prepare certain 3-isothiazolonecompositions free of nitrosamine precursors or nitrosamines.

It is another object of this invention to prepare aqueous3-isothiazolone solutions which are substantially free of nitrosaminesor nitrosamine precursors that can be converted to nitrosaminecompounds.

It is a further object of the present invention to furnish processes formaking 3-isothiazolones which either inhibit the formation ofnitrosamine precursors or, alternatively, which can be utilized toremove nitrosamine precursors before they are subjected to nitrosatingconditions.

Further objects will be obvious from the description which follows.

Except where stated otherwise herein, all percentages are by weight.

In preparing industrial biocides by amidation of the usual disulfideintermediates (e.g., dimethyl-3,3-dithiodipropionate), we find typicallevels of nitrosamine precursors between about 0.5% (5,000 ppm) andabout 1.1% (11,000 ppm) by weight in the amide product (the amide).After the amidated intermediate is chlorinated, filtered, neutralized,dissolved in water together with a metal nitrate stabilizer andheat-treated to remove by-product impurities, the final product containsabout 6%-16% (by weight of the original precursor) of a nitrosamine,that is, in the case of an original precursor content of 5,000 ppm, thefinal product has been found to contain typically 750 ppm ofnitrosamine. Because of the high dilution factor in industrialapplications, under use conditions the nitrosamine is rarely present inconcentrations greater than parts per billion.

Among the most effective biocides for inhibiting bacterial growth is a3-isothiazolone mixture comprised mainly of5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one(mixture dependent upon chlorination conditions), wherein thechlorinated species is between 60% and 90% by weight of the total activeingredients (AI). The process of manufacture includes the following:##STR3##

The first reaction above (1) produces a mixture containing about 95%mono-, di- and tri-thiodiamides and methanol. Upon cleavage of thedisulfide (during amidation), N-methylacrylamide by-product is believedto be formed. Conjugate addition of monomethylamine to this cleavageby-product may lead to the formation of the principal nitrosamineprecursor, N-methyl-3-(N'-methylamino) propionamide by the followingprobable reaction:

    CH.sub.3 NH.sub.2 +CH.sub.3 NHCOCH=CH.sub.2 -->CH.sub.3 NHCH.sub.2 CH.sub.2 CONHCH.sub.3 (nitrosamine precursor, MMAP)                (4)

N-methylacrylamide will also theoretically add to MMAP produced byreaction (4) above according to the following: ##STR4## Both of theabove nitrosamine precursors have been identified as being present inthe intermediate amide produced when amidating a disulfide startingmaterial. The nitrosamine precursors remain with the AI throughchlorination, neutralization and formulation of the 3-isothiazolonecomposition until the metal nitrate salt is added, at which timenitrosation takes place (principally during heat treatment) to form anitrosamine, e.g.: ##STR5##

The amidation reaction (1) is conducted in an organic solvent, eitheraliphatic or aromatic or mixtures thereof. Illustrative of the solventsused are methanol, toluene and laktane. Laktane is a commercial (Exxon)hydrocarbon solvent with a flash point of 25° F., a b.p. range of102°-108° C., and having the composition:

paraffins: 28% w/w

cycloparaffins: 54% w/w

toluene: 18% w/w

The disulfide amide reaction mixture resulting from amidation has a highsolids content. Chlorination of the filtered "amide" mixture to form thecyclic 3-isothiazolone hydrochloride mixture (2) is conducted with theamide in a concentrated slurry in an organic solvent typically toluene,perchloroethylene, ethyl or tributyl acetate; reaction preferablyinvolves concurrently feeding chlorine gas in the proper molar ratio(3-6, preferably 5, mols Cl₂ /l mol of amide) to the amide slurry in areactor.

An aqueous slurry of magnesium oxide may be used to neutralize thefiltered 3-isothiazolone hydrochloride reaction mixture to form thetechnical grade product. A metal nitrate stabilizer compound issubsequently added to the technical grade product prior to a final heattreatment step. Heat treatment is effective for removing or decomposingby-products. Other desirable steps in the preparation of the commercial3-isothiazolone biocides will be illustrated in the subsequent examplesor may be found in the prior art patents cited elsewhere herein,particularly U.S. Pat. No. 3,849,430.

We have now discovered that nitrosamines can be efficiently eliminatedfrom 3-isothiazolone products by (I) removing the nitrosamine precursorfrom the amide intermediate reaction mixture or by (II) inhibitingformation of the nitrosamine precursor during the amidation reaction.Alternative processes have been developed for each of (I) and (II).

The stabilized 3-isothiazolone compositions which can be preparedaccording to the processes of the present invention are "substantiallyfree" of nitrosamine precursors and nitrosamines, that is, they containless than about 100 ppm of such materials, preferably less than 50 ppm.Even more preferred for sensitive applications or uses which requireonly minimal dilution, are compositions containing less than 20 ppm ofprecursors and nitrosamines. As will be demonstrated hereinafter, it iseven possible to produce compositions with no detectable nitrosamine orprecursor compounds.

Removal or partial removal of the precursor from the amide intermediatemay be accomplished by separation techniques such as (a) ion exchange,(b) crystallization or recrystallization, or (c) solvent extraction(filtration and washing). These techniques are useful with the amidereaction mixture produced from a disulfide intermediate according to theprior art commercial process, or when utilizing an alternative processdisclosed herein (below) for inhibiting formation of the nitrosamineprecursor. When the 3-isothiazolone product must be essentiallynitrosamine-free, as with cosmetic products, a combination of the twotechniques is often to be preferred.

Recrystallization of N,N'-dimethyl-3,3'-dithiodepropionamide, from2-propanol effectively removes the nitrosamine precursorN-methyl-3-(N'-methylamino)propionamide from the reaction mixture of thedisulfide and methylamine (see Example 3 below). Filtration and methanolwashing of the N,N'-dimethyl-3,3'-dithiodiprionamide wetcake (seeExample 4, below) reduces the precursorN-methyl-3-(N'-methylamino)propionamide level from 5000 ppm to 400 ppm.

Removal of the nitrosamine precursor by selective ion exchange of thereaction mixture is also effective. Treatment of a methanolic solutionof N,N'-dimethyl-3,3'-dithiodipropionamide with a sulfonic acid cationexchange resin (Amberlyst 15, a trademark of Rohm and Haas Company,Philadelphia, Pa.) provides good removal ofN-methyl-3-(N'methylamino)propionamide from the reaction mixture of thedisulfide with monomethyl amine (see reaction 1, above). The resin maybe regenerated with methanolic aqueous hydrogen chloride (Example 5,below). The ion exchange process may be represented as follows: ##STR6##The final product 3-isothiazolone made from the ion exchange-treatedintermediate has a much reduced nitrosamine content.

Formation of the nitrosamine precursors can be inhibited by use of anucleophilic scavenger during the amidation reaction or by selection ofdifferent intermediates for the amidation reaction. Nucleophilicscavengers useful by the process of the invention are materials whichare generally (a) more active than an amine in a Michael additionreaction but (b) which do not degrade the reactants or reaction productof the amidation (see Example 7 below). Most aliphatic and aromaticmercaptans are useful in the addition reaction to N-alkylacrylamideintermediates, which are the reactive compounds responsible forproducing the principal nitrosamine precursors (see reactions 4 and 5above). Other Michael addition reactants, such as sodium or potassiumsalts of alcohols are generally not as desirable because of their highreactivity with other starting materials. A higher concentration of thenucleophilic scavenger in the amidation reaction leads to proportionallygreater reduction of the nitrosamine precursors: ##STR7##

The inherent avoidance of nitrosamine precursor when a mercaptanintermediate is selected in place of the normal disulfide intermediatein the amidation reaction is an important and unexpected finding of thepresent invention. A preferred mercaptan intermediate has the formula:##STR8## wherein X and Z have the meaning set forth above. Theintermediate is essentially half of the conventional disulfide reactant(see reaction A above) used in the amidation reaction but, surprisingly,yields a product much lower in nitrosamine precursor, presumably by thesame mechanism as postulated above for the nucleophilic scavengers. Inthe case of the isothiazolone biocide mixture illustrated above (inreactions 1-5) the mercaptan which may be used has the formula HSCH₂ CH₂COOCH₃ and is known as "MMP" (methyl-3-mercaptopropionate). Theremarkable reduction in nitrosamine precursor in the amide when usingMMP in place of the usual disulfide is illustrated in the followingtable:

                  TABLE I                                                         ______________________________________                                        Precursor* (CH.sub.3 NHCH.sub.2 CH.sub.2 CONHCH.sub.3) Level in               Intermediate Compared to MMP Process Intermediate                                           Precursor in                                                                  Amide Reaction                                                  Intermediate  Mixture                                                         Batch         (ppm)                                                           ______________________________________                                        Amidated Disulfide Intermediate                                               (Reaction 1 above)                                                            1             5,600                                                           2             4,800                                                           3             6,400                                                           4             4,500                                                           5             5,000                                                           6             10,100                                                          7             11,400                                                          8             5,700                                                           9             9,400                                                           10            6,700                                                           Amidated MMP Intermediate                                                     (HSCH.sub.2 CH.sub.2 CONHCH.sub.3)                                               1, 2, 3        21, 24, 31                                                  4             43                                                              5             37                                                              6             80                                                              7             60                                                              8             70                                                              9             <30                                                             10            <30                                                             11            110                                                             ______________________________________                                         *Precursor = MMAP (see reaction 4, above).                               

Other advantages of using a mercaptan intermediate (e.g., MMP) may befound in the reaction product of the mercaptan and the amine. In thecase of MMP, the amide is a liquid rather than a solid, as is the casewith a disulfide intermediate (see Example 8). The difficulties usuallyencountered in handling, agitating, pumping and reacting a slurry arethus avoided. Further, use of the mercaptan intermediate reduces theamount of halogen (chlorine) needed for cyclization of the amide fromthe usual 3.0-6.0 mols/mol of intermediate to 2.8-3.4 mols, preferably3.0 mols, per mol of intermediate.

The nitrosamine precursor by-product of the amidation reaction carriesthrough to the final product, but the dilution of the AI in the productresults in a lower concentration. Thus, the ultimate stabilized3-isothiazolone composition will normally have a nitrosamineconcentration of about 15% of the precursor concentration found in theamide. Table II illustrates the different concentrations of the majornitrosamine precursor (MMAP) in the amide compared to the nitrosamine(MMNP) in the corresponding stabilized (nitrate added/heat treated)product for a mixture containing (as the AI)5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-oneproduced from an MMP starting material of the present invention.

                  TABLE II                                                        ______________________________________                                        Precursor (MMAP) in Amide Intermediate v.                                     Nitrosamine in Stabilized Product                                                         Stabilized                                                        Amide Intermediate   3-Isothiazolone                                          Sample No.   MMAP (ppm)  MMNP* (ppm)                                          ______________________________________                                        1            80                      <3                                       2            <30                     2.0                                      3            60                      <1.0                                     4            70                      7.3                                                                            2.3                                     5            <30         **                                                                                        3.8                                      6            <30                     1.9                                                                           10.6                                     7            110         **          3.4                                                                           8.3                                                                            1.0                                     8            21          **                                                                                        1.0                                      9            24                      1.0                                                                            1.0                                     10           31          **                                                                                        2.0                                      11           31                      10.3                                                                          11.6                                     12           43          **          7.9                                                                           3.6                                                                           6.0                                      13           37          **          5.3                                                                           5.6                                      ______________________________________                                         *MMNP = Nmethyl-3-(Nmethyl-Nnitroso) aminopropionamide (a nitrosamine)        produced by nitrosating MMAP.                                                 **Intermediate divided for multiple conversions to the final product.    

The mechanism for nitrosamine reduction in the above MMP process appearsto reside in the reduction of the nitrosamine precursorN-methyl-3-(N'-methyl)aminopropionamide (MMAP) in the amide. The amidedisulfide source for the postulated N-methylacrylamide intermediate(reaction 4 above) is reduced to a minor reaction by-product. Also, theMMP starting material and N-methyl-3-mercaptopropionamide appear tocompete successfully with monomethylamine to consume N-methylacrylamideand hence avoid formation of MMAP. These postulated alternative routesare as follows:

    CH.sub.3 NHCOCH=CH.sub.2 +HSCH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 -->CH.sub.3 NHCOCH.sub.2 CH.sub.2 SCH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3

    CH.sub.3 NHCOCH=CH.sub.2 +HSCH.sub.2 CH.sub.2 CONHCH.sub.3 -->(CH.sub.3 NHCOCH.sub.2 CH.sub.2).sub.2 S

The net result is the reduction of MMAP levels from about 5,000-11,000ppm for the disulfide process to about <100 ppm in the MMP process.

The following specific examples are offered to illustrate this inventionbut are not to be construed as limitations thereof.

EXAMPLE 1 Comparative example--illustrates state of the art Step 1:Amidation Preparation of N,N'-dimethyl-3,3'-dithiodipropionamideIntermediate

Charged to a vapor-tight reaction kettle wasdimethyl-3,3'-dithiodipropionate (101 lb, 0.424 mol), laktane (131 lb.)and methanol (5.06 lb). The mixture was cooled to 15°-20° C. withagitation. Monomethylamine (32.8 lb, 1.06 mol) was added beneath thesurface of the reaction mixture with agitation at 15°-20° C. and 5-10psi over 2 hr. After completing the monomethylamine addition, themixture was stirred at 15°-20° C. for 10 hr. A thick, pale-yellow slurrywas obtained. At this time the unreacted monomethylamine and methanolby-product were distilled from the mixture at ˜100 mmHg. After thedistillation period, the yellow slurry was rotary vacuum dried andisolated without washing to provide crude, dryN,N'-dimethyl-3,3'-dithiodipropionamide (100 lb, 100% yield), containing5,000 ppm N-methyl-3-(N'-methyl)aminopropionamide.

Step 2: Chlorination (oxidation cyclization) Preparation of a mixture of5-chloro-2-methyl-4-isothiazolin-3-one hydrochloride and2-methyl-4-isothiazolin-3-one hydrochloride

A slurry of the crude N,N'-dimethyl-3,3'-dithiodipropionamide reactionproduct of Step 1 was diluted with toluene and chlorinated to yield aslurry containing 5-chloro-2-methyl-4-isothiazolin-3-one hydrochlorideand 2-methyl-4-isothiazolin-3-one hydrochloride and mother liquor.

Step 3: Filtration and Neutralization

The chlorinated slurry from Step 2 was filtered and neutralized with amagnesium oxide slurry to form the tech grade product.

Step 4: Formulation and Heat Treatment (Stabilization)

The Tech product made in Step 3 was formulated by adding magnesiumnitrate hexahydrate, and transferring the mixture to a heat treatmentkettle equipped with an agitator and a reflux condenser.

The product was heat treated for 4 hours and then allowed to cool toroom temperature. The batch was filtered to remove small amounts ofsuspended solids. This gave a product with the following AI analysis:

    ______________________________________                                        Components             Wt. %                                                  ______________________________________                                        5-chloro-2-methyl-4-isothiazolin-3-one                                                               9.8                                                    2-methyl-4-isothiazolin-3-one                                                                        6.0                                                    Nitrosamine.sup.a      750 ppm                                                ______________________________________                                         .sup.a Nmethyl-3-(Nmethyl-Nnitroso)aminopropionamide (MMNP).             

EXAMPLE 2 Comparative Example/Illustrates State of the Art and Removalby Filtration Step 1: Amidation

Into a three-liter, 4-necked flask equipped with a mechanical stirrer,thermometer, gas dispersion tube and dry ice condenser with nitrogeninlet adapter, was placed dimethyl-3,3'dithiodiopropionate (1,062.5 g,4.46 mol), toluene (535.0 g) and methanol (55.0 g). The apparatus waspurged with nitrogen and the mixture was cooled to 10° C.Monomethylamine (346.0 g, 11.14 mol) was added through the gasdispersion tube with stirring at 10°-20° C. over 2 hrs. After completingthe monomethylamine addition, the mixture was stirred at 20° C. for 20hrs. to complete the reaction. A thick, pale yellow slurry was obtained.At this time the unreacted monomethylamine and methanol by-product weredistilled from the mixture at ˜100 mmHg. The crude dryN,N'-dimethyl-3,3'-dithiodipropionamide intermediate (1,022.4 g, 97%yield) contained 11,000 ppm N-methyl-3-(N'-methyl)aminopropionamide.

A portion of the intermediate slurry was filtered, washed with tolueneand dried. The dry intermediate contained 8,000 ppm ofN-methyl-3-(N'-methyl)aminopropionamide.

Step 2: Chlorination Preparation of a mixture of5-chloro-2-methyl-4-isothiazolin-3-one hydrochloride and2-methyl-4-isothiazolin-3-one hydrochloride

A one-liter 3-necked round bottom flask was equipped with an overheadagitator, a feed line (outlet) and a condenser with a drying tube. Intothis flask, 635.8 g of a slurry ofN,N'-dimethyl-3,3'-dithiodipropionamide (with 8,000 ppm precursor) intoluene was placed and agitated.

A one-liter, 5-necked resin kettle (i.e., a chlorinator) was equippedwith an agitator, a fritted glass gas dispersion tube for Cl₂ inlet, athermometer, a condenser attached to an off-gas scrubber, and a feedline-inlet for intermediate slurry. The kettle was jacketed forice-water circulation. The cooling system maintained the chlorinationbatch at 25°-30° C. The chlorinator was charged with a 108 g of tolueneas a heel, and the agitator was started.

The slurry and Cl₂ were fed concurrently at a molar feed ratio of 5.2.Thus, 453 g of the slurry was charged over a 55-minute period at a rateof about 8.2 g/min., while 227 g of Cl₂ (gas) was fed at a rate of about4.1 g/min., using a calibrated flowmeter.

Step 3: Filtration and Neutralization

To the agitated chlorination slurry 20 g of water was added gradually.After 10 min. of agitation, the batch was allowed to settle, and themother liquor was siphoned out using a dipstick. An additional 45 g ofwater was added, and additional mother liquor was removed.

To the hydrochloride wet cake was added 116 g of water. The mixture wasneutralized to a pH 4.5 by gradually adding an aqueous MgO slurry. Theneutralized material was transferred to a separatory funnel and a 469 gof an aqueous Tech grade was separated from the organic layer:

    ______________________________________                                        Active Ingredient (Tech)                                                                             Wt %                                                   ______________________________________                                        5-chloro-2-methyl-4-isothiazolin-3-one                                                               17.1                                                   2-methyl-4-isothiazolin-3-one                                                                        5.5                                                    ______________________________________                                    

Step 4: Formulation and Heat Treatment (Stabilization)

The pH of the above Tech was adjusted to 2.9, and 46.5 g of magnesiumnitrate hexahydrate and 7.24 g of water were added to 100 g of the AIwith agitation to give a solution with the following composition:

    ______________________________________                                        Component    Nominal Conc., Wt %                                              ______________________________________                                        Total AI     15.2                                                             Mg(NO.sub.3).sub.2                                                                         17.4                                                             ______________________________________                                    

The above formulated product was transferred to a 500 ml 3-necked roundbottom flask equipped with an overhead agitator, a water-cooledcondenser and a thermometer attached to a themo-watch and pneumatic potlifter assembly supporting a heating mantle.

The formulated product was heat-treated at 95° C. for 4 hrs. Theproduct, 153.7 g, was filtered to remove any trace amounts of solids,and analyzed.

    ______________________________________                                        Analysis:                                                                     Components            Wt %                                                    ______________________________________                                        5-chloro-2-methyl-4-isothiazolin-3-one                                                              10.1                                                    2-methyl-4-isothiazolin-3-one                                                                       5.0                                                     Nitrosamine*          1200      ppm                                           ______________________________________                                         ##STR9##                                                                 

EXAMPLE 3 Recrystallization of CrudeN,N'-Dimethyl-3,3'-dithiodipropionamide (Removal of NitrosaminePrecursor)

Crude amide intermediate (disulfide produced/see Example 1, above), 1400g, was dissolved in 1750 g of boiling 2-propanol and the solution wasfiltered rapidly through a pre-heated Buchner funnel. The filtrate waskept overnight at 5°-10° C. in a refrigerator. The crystalline productwas collected by filtration on a Buchner funnel, washed with a 560 gportion of cool methanol and dried on a rotary evaporator (35° C./20 mmof Hg/2 hours) to give 995 g of 99.1% pure intermediate m.p. 113°-115°C.

Next, 789.2 g of the crystallized amide intermediate was recrystallizedfrom 2300 g of boiling 2-propanol to give 685.6 g of 99.9⁺ % w/w amideintermediate, m.p. 113°-115° C.

Anal. calcd. for C₈ H₁₆ N₂ O₂ S₂ : C,40.65; H,6.82; N,11.85; O,13.54;S,27.13. Found: C,40.29; H,6.83; N,11.61; O,13.57; S,27.38.

The N-methyl-3-(N'-methyl)aminopropionamide content was 0 ppm.

Nitrosamine-Free Product, Using Pure Amide Intermediate

Following the chlorination procedure described in Example 2, 152.6 g ofrecrystallized pure amide was chlorinated; the chlorination slurry wasfiltered and neutralized to give 537.9 g of Tech product, with a totalAI of 21.5%.

A 350 g portion of this Tech product was formulated by dissolving 145.5g magnesium nitrate hexahydrate in the product. The formulated productwas heat-treated at 95° C. for 4 hours to give 495 g of 3-isothiazolonecomposition with the following ingredients:

    ______________________________________                                        5-chloro-2-methyl-4-isothiazolin-3-one                                                               10.3%                                                  2-methyl-4-isothiazolin-3-one                                                                        5.0%                                                   Nitrosamine, ppm       0                                                      ______________________________________                                    

Nitrosamine-free Products, from Pure Active Ingredient Isothiazolones

Alternatively, pure 2-methyl-4-isothiazolin-3-one, and pure5-chloro-2-methyl-4-isothiazolin-3-one, can be obtained and formulatedas above to give pure product. This material, with or without 95° C./4hour heat treatment, was found to be nitrosamine-free.

EXAMPLE 4 Precursor Removal by Solvent Extraction

Into a three-liter, 4-necked flask equipped with a mechanical stirrer,thermometer, gas dispersion tube and dry ice condenser with nitrogeninlet adapter, was placed dimethyl-3,3'-dithiodipropionate (1062.5 g,4.45 mol) toluene (295.0 g) and methanol (295.0 g). The apparatus waspurged with nitrogen and the mixture was cooled to 10° C.Monomethylamine (304.7 g, 9.81 mol) was added through the gas dispersiontube with stirring at 10°-20° C. over 2 hrs. After completing themonomethylamine addition, the mixture was stirred at 20° C. for 20 hrs.to complete the reaction. A thick, pale yellow slurry was obtained. Atthis time, the unreacted monomethylamine, methanol and some toluene weredistilled from the mixture at 100 mmHg over 8 hrs. The resulting slurrywas rotary evaporated to give crudeN,N'-dimethyl-3,3'-dithiodipropionamide (1058.9 g, 100% yield),containing 5,000 ppm N-methyl-3-(N'-methyl)aminopropionamide. A portionof the crude product (353.0 g was slurried in 784.5 g toluene) andvacuum filtered through a 2,000 ml course sintered glass funnel to givea toluene wet cake (419.1 g). The toluene wet cake was washed with cold(0° C.) methanol (352.4 g) to give the methanol wet cake (315.2 g). Themethanol wet cake was dried in a vacuum desiccator at ambienttemperature to give the washed, dried amide intermediate (251.1 g), 71%recovery), containing 400 ppm N-methyl-3-(N'-methyl)aminopropionamide.

Following the process steps 2, 3 and 4 described in Example 2, above,the dry N,N'-dimethyl-3,3'-dithiodipropionamide was converted to give260 g of 3-isothiazolone product (pH 2.1) with the followingcomposition:

    ______________________________________                                        Components             Wt %                                                   ______________________________________                                        5-chloro-2-methyl-4-isothiazolin-3-one                                                               12.0                                                   2-methyl-4-isothiazolin-3-one                                                                         2.7                                                   Nitrosamine            25 ppm                                                 ______________________________________                                    

EXAMPLE 5 Precursor Removal by Ion Exchange

Unfiltered laktane (Example 1, above) processN,N'-dimethyl-3,3'-dithiodipropionamide was rotary evaporated in thelaboratory to constant weight. The dried intermediate contained 10,000ppm N-methyl-3-(N'-methyl)aminopropionamide.

Conditioned Amberlyst 15 sulfonic acid ion exchange resin (22.2 g of45.1% w/w material in water, 10.0 g of dry resin) was washed into a 50ml buret (1 cm diameter) with methanol (25 ml). The resin was rinsed onthe column with methanol (500 ml) to give a resin bed volume of 28 ml.

The dry intermediate was dissolved in methanol to give a 19.9% w/wsolution. This solution was passed through the resin column at ambienttemperature and atmospheric pressure at a flow rate of 9.21 bed volumesper minute. The resin became saturated withN-methyl-3-(N'-methyl)aminopropionamide and break-through occurred aftercollecting 34 bed volumes. The total quantity of methanolic solutiontreated up to the break-through point was 737.2 g. Rotary evaporation ofthe eluent allowed recovery of the crudeN,N'-dimethyl-3,3'-dithiodipropionamide (146.5 g, 99.9% recovery),containing 380 ppm N-methyl-3-(N'-methyl)aminopropionamide.

EXAMPLE 6 Precursor Removal by Ion Exchange

Into a one-liter, 4-necked flask equipped with a mechanical stirrer,thermometer, gas dispersion tube and dry ice condenser with nitrogeninlet adapter, was placed dimethyl-3,3'-dithiodipropionate (215.5 g,0.904 mol) and methanol (118.0 g). The apparatus was purged withnitrogen and the mixture was cooled to ˜10° C. Monomethylamine (70.0 g,2.25 mol) was added through the gas dispersion tube with stirring at10°-20° C. over 2 hrs. After completing the addition, the mixture wasstirred at 20° C. for 20 hrs. to complete the reaction. A thick, paleyellow slurry was obtained. At this time the unreacted monomethylamineand some methanol were distilled from the mixture at ˜100 mmHg. Afterdistillation, a portion of the slurry (17.2 g) was rotary evaporated toconstant weight (8.0 g), giving the concentration of crude product inthe slurry at 47% w/w. The 47% w/w slurry was 436.0 g, corresponding to204.9 g of crude N,N'-dimethyl- 3,3'-dithiodipropionamide (96% yield).The dry, crude product contained 9,000 ppmN-methyl-3-(N'-methyl)aminopropionamide.

Conditioned Amberlyst 15 sulfonic acid ion exchange resin (22.2 g of45.1% w/w material in water, 10.0 g of dry resin) was washed into a 50ml buret (1 cm diameter) with methanol (25 ml). The resin was rinsed onthe column with methanol (500 ml) to give a resin bed volume of 28 ml.

The 47% w/w slurry in methanol was further diluted with methanol toprovide a 20.0% w/w solution. This solution was passed through the resincolumn at ambient temperature and atmospheric pressure at a flow rate of0.21 bed volumes per minute. The resin became saturated withN-methyl-3-(N'-methyl)aminopropionamide and break-through occurred aftercollecting 18 bed volumes of eluent. The total quantity of methanolicN,N'-dimethyl-3,3'-dithiodipropionamide solution treated up to thebreak-through point was 315.0 g (63.0 of AI). Rotary evaporation of theeluent allowed recovery of the crudeN,N-methyl-3,3'-dithiodipropionamide (63.0 g, 100% recovery), containing300 ppm N-methyl-3-(N'-methyl)aminopropionamide.

Following the procedure described in Example 2, 73.3 g of theabove-mentioned intermediate was chlorinated, filtered and neutralizedto give 217.5 g of Tech grade product.

A 60 g sample of this Tech grade product was formulated with 29.4 g ofMg(NO₃)₂.6H₂ O and 7.8 g of water. The formulated product washeat-treated at 95° C. for 4 hours, cooled and filtered to give about 97g of 3-isothiazolone with the following composition:

    ______________________________________                                                             Wt %                                                     ______________________________________                                        5-chloro-2-methyl-4-isothiazolin-3-one                                                               11.7                                                   2-methyl-4-isothiazolin-3-one                                                                        3.5                                                    Nitrosamine, ppm       33                                                     ______________________________________                                    

EXAMPLE 7 Inhibition of Precursor by Nucleophilic Scavenger

Following the procedure of Example 2, Step 1,dimethyl-3,3'-dithiodipropionate (212.5 g, 0,892 mol),methyl-3-mercaptopropionate (18.4 g, 0.153 mol) and monomethylamine(69.0 g, 2.22 mol) were reacted. The intermediate slurry was rotaryevaporated to give crude N,N'-dimethyl-3,3'-dithiodipropionamide (224.1g, 98% crude yield), containing 1,000 ppmN-methyl-3-(N'-methyl)aminopropionamide.

This Example has been repeated using higher levels of a nucleophilicscavenger. The results of these experiments have established anessentially proportional reduction of nitrosamine precursor as higherconcentrations of nucleophilic scavenger were used.

EXAMPLE 8 Inhibition of Precursor by Mercaptan Reactant Route Step 1:Preparation of N-methyl-3-mercaptopropionamide (MMPA)

Into a one-liter, 4-necked flask equipped with a mechanical stirrer,thermometer, gas dispersion tube, and dry ice condenser with nitrogeninlet adapter, was placed methyl-3-mercaptopropionate (MMP, 504.7 g,4.20 mol). The vessel was purged with nitrogen and the liquid was cooledto 10° C. Monomethylamine (163.0 g, 5.25 mol) was added through the gasdispersion tube with stirring at 10°-20° C. over 1 hr. After completingthe addition, the mixture was stirred at 20° C. for 20 hrs. to completethe reaction. At this time the methanol by-product and unreactedmonomethylamine were distilled from the mixture at ˜100 mmHg. Theresulting mixture was rotary evaporated to give crudeN-methyl-3-mercaptopropionamide (500.8 g, 100% yield), containing <30ppm N-methyl-3-(N'-methyl)aminopropionamide.

Step 2: Chlorination

The procedure described in Example 2 was modified in thatN-methyl-3-mercaptopropionamide (MMPA) was used in place ofN-N'-dimethyl-3,3'-dithiodipropionamide. Thus, a 31% solution ofN-methyl-3-mercaptopropionamide in toluene and Cl₂ were fed concurrentlyat a molar feed ratio of about 3.2.

To 59.5 g of a toluene heel, 398.9 g of 31% MMPA solution was chargedover a period of 55 minutes at a rate of 7.1 g per minute, while a 220 gof Cl₂ was fed concurrently at a feed rate of 4.0 g per minute.

Step 3: Filtration and Neutralization

Following the procedure described in Example 2, the chlorination slurrymade above was worked-up and neutralized to give 355 g of Tech grade3-isothiazolone with the following composition:

    ______________________________________                                        5-chloro-2-methyl-4-isothiazolin-3-one                                                               16.0%                                                  2-methyl-4-isothiazolin-3-one                                                                        5.3%                                                   ______________________________________                                    

Step 4: Formulation and Heat Treatment (Stabilization)

Following the procedure described in Example 2, a 200 g portion of theTech grade material made above was formulated by adding 87.7 gMg(NO₃)₂.6H₂ O and 2.1 g water. The formulated product was heat-treated,cooled and filtered to give 289 g of 3-isothiazolone product with thefollowing composition:

    ______________________________________                                        5-chloro-2-methyl-4-isothiazolin-3-one                                                                 12.2%                                                2-methyl-4-isothiazolin-3-one                                                                           3.9%                                                Nitrosamine               3.9 ppm                                             ______________________________________                                    

EXAMPLE 9 Preparation of N-(n-octyl)-3-mercaptopropionamide by MercaptanReactant Route

In a small multi-necked reaction vessel equipped with a magnetic stirrerand gas inlet was placed isopropanol (2 ml), methyl-3-mercaptopropionate(2.0 g, 16.64 mmol), and n-octylamine (2.19 g, 16.94 mmol). The reactionvessel was connected to a trap containing bleach to trap mercaptanvapors, and the reaction was stirred for 19.5 hours while the reactiontemperature was held at 30°-35° C. Methylene dichloride was added andthe crude product was transferred to a round bottom flask. Evaporationof the solvent under reduced pressure yielded crudeN-(n-octyl)-3-mercaptopropionamide as an oily white solid in essentiallyquantitative yield.

The N-(n-octyl)-3-mercaptopropionamide of Example 9 may be converted tothe corresponding 2-n-octyl-isothiazolin-3-one substantially free ofnitrosamine and nitrosamine precursor.

EXAMPLE 10 Preparation of N-propyl-3-mercaptopropionamide by MercaptanReaction Route

In a small multi-necked reaction vessel equipped with a magneticstirrer, reflux condenser, and gas inlet was placed isopropanol (2 ml),n-propylamine (1.00 g, 16.92 mmol), and methyl-3-mercaptopropionate (2.0g, 16.64 mmol). The reaction vessel was connected to a trap containingbleach, and the reaction was stirred at 30°-35° C. for 19.5 hours. Thecrude reaction mixture was concentrated under reduced pressure to removeexcess amine, solvent and methanol. A light yellow liquid was obtained,with essentially all N-propyl-3-mercaptopropionamide.

The N-propyl-3-mercaptopropionamide of Example 10 may be converted tothe corresponding N-propylisothiazolin-3-one substantially free ofnitrosamine and nitrosamine precursor.

EXAMPLE 11 Combinations of Inhibition and Removal of Precursor

Following the procedure of Examples 1-8 above, combined use of theillustrated techniques has been employed to produce isothiazoloneproducts having drastically reduced or no nitrosamines or precursorswhatsoever.

We claim:
 1. A process for preparing a biologically active, metalnitrate salt-stabilized, 3-isothiazolone compositions substantially freeof nitrosamine impurities and precursors thereof whichcomprises:preparing a biologically active 3-isothiazolone substantiallyfree of a by-product compound containing an amine moiety capable ofbeing nitrosated to a nitrosamine, or a nitrosamine compound derivedtherefrom, which 3-isothiazolone may be represented by the formula:##STR10## wherein R is hydrogen and R¹ is selected from hydrogen andchlorine; and Y is methyl, where said 3-isothiazolone is prepared by aprocess in which formation of said undesirable by product compound isavoided comprising the steps of (A) reacting methyl-3-mercaptopropionatewith CH₃ NH₂ to form N-methyl-3-mercaptopropionamide; (B) cyclizing saidN-methyl-3-mercaptopropionamide with a chlorinating agent to form said3-isothiazolone; and (C) adding to said 3-isothiazolone aring-stabilizing metal nitrate salt in an amount sufficient to stabilizethe ring of the 3-isothiazolone.
 2. The process of claim 1 wherein thestabilizing nitrate salt in the 3-isothiazolone reaction mixture isselected from the group consisting of sodium nitrate, potassium nitratecalcium nitrate, magnesium nitrate, copper nitrate, ferric nitrate,ferrous nitrate, nickel nitrate, zinc nitrate, barium nitrate, manganesenitrate, cobalt nitrate, and mixtures thereof.
 3. The process of claim 1wherein the 3-isothiazolone consists essentially of a mixture of5-chloro-2-methyl-4-isothiazolin-3-one and2-methyl-4-isothiazolin-3-one.